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CA1096385A - 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4- imidazolidinone - Google Patents

5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4- imidazolidinone

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Publication number
CA1096385A
CA1096385A CA286,134A CA286134A CA1096385A CA 1096385 A CA1096385 A CA 1096385A CA 286134 A CA286134 A CA 286134A CA 1096385 A CA1096385 A CA 1096385A
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CA
Canada
Prior art keywords
dimethyl
imidazolidinone
indol
methylimino
ylmethylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA286,134A
Other languages
French (fr)
Inventor
Peter T. Murphy
Robert J. Wells
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
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Publication of CA1096385A publication Critical patent/CA1096385A/en
Expired legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to the novel 5-(indol-3--ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone of the formula E-isomer or Z-isomer

Description

l~G3~:~5 The invention relates to a novel cyclic compound, namely 5-(indol-3-ylmethylene)-1,3,-dimethyl-2-methylimino-4-imidazolidinone and to a process for the manufacture thereof.

The compound can exist in isomeric forms, e.g. the : E-isomer of the formula H

and the Z-isomer of the formula / ~ \ CE Z-l G3~35 The compound of formula E-l, i.e. (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone, exists in low quantities in, and can be isolated by extraction from, a sponge belonging to the order Dictyoceratida, which can be collected on the Australian seacoasts. The substantially pure (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone, i.e. said compound free from the other compounds contained in the sponge, thus constitutes a further feature of the present invention. 5-(Indol-3-ylmethylene)-1,3-dimethyl-2-- methylimino-4-imidazolidinone can be prepared in accordance with the invention by a process characterized in that a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-methylimino-4-imidazolidinone, or b) 5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazo-lidinone is reacted with a methylating agent.

In another aspect the invention provides a process for the preparation of (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone characterized in that a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-methylimino-4-imidazolidinone, and the E-product is separated from the resulting E-Z mixture; or b) (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone is reacted with a methylating agent.

,3~

In yet another aspect the invention provides a process for the preparation of (Z)-5-(indol-3-ylmethylene)-; 1,3-dimethyl-2-methylimino-4-imidazolidinone characterized in that a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-methylimino-4-imidazolidinone, and the Z-product is separated from the resulting E-Z mixture; or b) (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone is reacted with a methylating agent.

`~ - 3 -: , , . ;

`'',.

1~963~S ~-The imidazolidinone starting material utilized in embodiment (a) of this process has the formula ~0 ~N~N~ ¦

The E- and Z-isomers of the imidazolidinone starting materials utilized in embodiment (b) of this process have the formulae ~ ~N~l~ E 2 - H
~H3 lo and NH
respectively.

~C~9638S

The condensation of an indole-3-aldehyde derlvatlve with compound II,in accordance with embodiment (a) of the present process, can be carried out in a manner known per se, e.g. by heating e~uimolar quantities of said starting materials in the presence of acondensation agent, at a temperature up to the reflux temperature of the reaction mixture, ~referably at a temperature of from about 50 to about 150C. Examples of condensation agents which can be utilized in the above reaction are ali~hatic carboxvlic acids and the alkali metal salts of these acids, e.g. acetic acid containing anhydrous sodium acetate, secondary or tertiary amines, e.g. piperidine, or mixtures thereof.

The methylation in accordance with embodiment (b) of the present process can be carried out in a manner known per se, for example by heating 5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone optionally substituted in position 6 by lower alkyl,with a methylating a~ent, such as methyl iodide, dimethyl sulfate or methylated derivatives-of dimethyl sulphoxide, in an inert solvent, such as diethyl ether or ethanol, at a temperature up to the reflux temperature of the ` reaction mixture.

5-(indol-3-ylmethvlene)-1,3-dimethvl-2-imino-4-imidazolidinone is novel and forms also part of the invention.
It can be prepared by condensing indole-3-aldehyde with ;3~5 1,3-dimethyl-2-imino-4-imidazolidinone, in a manner analogous to that described above for embodiment (a).

5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone has antidepressant activity. This can be demonstrated in warm-blood animals using standard procedure.

: . . . - . .

For example, the antagonism of tetrabenazine induced ptosis is demonstrated in male mice weighing 18-25 g. Groups of 10 mice each are administered tetrabenazine methanesulpho-nate at a dose of 100 mg/kg, one hour after oral administration of the compounds to be tested. One hour after tetrabenazine administration, each mouse is observed for the presence or absence of ptosis. An ED50 value for the antagonism of tetra-benazine induced ptosis is then determined. (E)-5-(Indol-3-ylmethylene)--1,3-dimethyl-2-methylimino-4-imidazolidinone was found to have an ED50 of 5 mg/kg.

1~963~5 7 _ 5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone has antidepressant properties qualitatively similar to those compounds such as imipramine, harmaline and pargyline, which are known for their therapeutic uses and properties. In contradistinction to these known compounds, 5-(indol-3-ylmethvlene)-1,3-dimethyl-2-methylimino-4-imidazolidinone has no anticholinergic or cardiovascular side effects. Furthermore, said known compounds are more toxic than 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone as can be seen from the following acute toxicity data, expressed in LD50 mg/kg in mice:

.

(E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-Compounds imidazolidinone imipraminepargyline harmaline _ LD50 i-p- 670 125 390 120 5-(Indol-3-y~tethylene)-1,3-dimeth,1-2-methylimino-4-imidazolidin-one is useful for the treatment of depressions. It can be used in medicine in the form of pharmaceutical pre~arations which contain it in association with a compatible pharmaceutical carrier, namely an oryanic or inorganic inert carrier material suitable for enteral, e.g. oral, or parenteral administration.

1~9~385 - B_ Examples of such carrier materials are water, gelatin, lactose, starch, talc, magnesium stearate, gums, vegetable oils and petroleum jelly. The pharmaceutical preparations can be made up in a solid form, e.g. as tablets, capsules, dragees or sup-positories, or in a liquid form, e.g. as solutions, emulsionsor suspensions. The pharmaceutical preparations may be sterilised and/or may contain compatible adjuvants such as preservatives, stabilising agents, flavouring agents, colouring agents, emulsifying agents, salts for varying the osmotic pressure or buffering agents.

- ~Convenient pharmaceutical dosage forms contain about . . .
1 to 100 mg of 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone. Convenient oral dosages are in the range of about 0,1 mg/kg per day to about 10 mg/kg per day.
Convenient parenteral dosages are in the range of about 0,01 mg/kg per day to about 0,5 mg/kg per day. However, the ranges mentioned can be extended upwards or downwards depending upon individual requirements.

~9~3~35 g Example 1 5 g of 1,3-dimethyl-2-methylimino-4-imidazolidinone and 5 g indole-3-aldehyde are refluxed in piperidine for 3 hours.
The reaction mixture is poured into 250 ml of water, stirred for 30 minutes, filtered, washed with water and dried. There are obtained 8,45 g of (E)-5-~ndol-3-vlmethylene)-1,3-dimethyl-
2-methylimino-4-imidazolldinone.

The product recrystallizes from methanol in form of yellow needles, m.p. 226,5-228C.

H n-m-r- (CD3cooD) ~ 9,Ol(lH,S), 7,78(1H,m~, 7,58 (lH,m), 7,30(2H,m), 6,87(1H,S), 3,33(3H,S), 3,22(3H,S), 3,13(3H,S).

The following data are obtained bv low resolution mass ; spectrometry:

M+ 268 (61,9%), 253 (21,6%), 170 (23,7%), 169 (33,0~), 155 (base peak), 128 (25,3%), 101 (19,1%).

Example 2 a) The ~reparation of the startinq material 255 mg of 1,3-dimethyl-2-imino-4-imidazolidinone hydriodide and 145 mg of indole-3-aldehyde are refluxed in 5 ml piperidine for 4 hours. After cooling, the reaction :

1~963~5 mixture is poured into 50 ml water. After stirring for 30 minutes the formed precipitate is filtered, washed with water and dried. There are obtained 205 mg of (E)-5-tindol-3-yl-methylene)-1,3-dimethyl-2-imino-4-imidazolidinone.

The product recrystallizes from methanol as fine, yellow needles, m.p. 231,8-233,1C.

b) The ~rocess 500 mg of(E~indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone are refluxed in methanol for 24 hours with 425 mg of methyl iodide. The product is chromatographed on silica gel and alumina. There are obtained 107 mg of(E~5-(indol-3-ylmethylene)-1,3-dimethvl-2-methylimino-4-imidazol-idinone.

Example 3 A mixture of 5.10 g of indole-3-carboxaldehyde, 5.64 g of dimethylcreatinine and 60 ml of pipe~dine was heated at reflux for 3 hrs, cooled to room temperature and poured into 350 ml of water. The precipitate was collected by filtration - and dried to give 8.2 g of yellow solid, m.~. 241-241.5,which consisted of a 9:1 mixture of E- and Z-isomers. By heating a solution of the crude product in 2 1 of methanol and 100 ml of piperidine at reflux for 2 hrs and removal of the solvents, a 1:1 mixture of E- and Z-isomers was obtained.

1~963~3S

A one-gram sam~le of the above mix~ure (1:1 ratio of isomers) was digested wi~h 20 ml of hot acetone and the soluble portion (565 mq) was applied directly to a column of 15 g of silica gel prepared in ethyl acetate. Elution was carried out with acetone collecting 20 ml fractions. Fractions 6, 7, and 8 were combined (144 mg) and crystallized from acetonitrile to afford 126 mg of (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino -4-imidazolidinone as a pale yellow solid, m.p.
241-242. The analytical sample was recrystallized from acetonitrile, m.p. 241-242 . Mass spectrum m/e 268; W (95 ethanol): 229nm ( 22,400), 271 nm (9200); 365 nm (22,450);
NMR (100 mHz, DMS0-d6): ~7.67 (s, lH, H-2), 6.75 (s,0.94 H, CH=C-C0, major*), 6.48 (s, 0.06 H, C~-CC0, minor*).

Corresponding data for the E-isomer, which was isolated by crystallization of 9:1 mixture of isomers from methanol/
methylene chloride: W (95% ethanol): 232nm ( 20,600), 276nm (6950) 394nm (22,600); NMR (100 mHz, DMS0-d6): ~ 8.72 (broad, lH, H-2); 6.47 (s, 0.67 H, CH=C-C0, major*), 6.30 (s, 0.33 H, CH=C-C0, minor*).

.
* Attributed to the isomers of the C=N-CH3.

1~i963~5 , Example A

Tablets of the following composition are manufactured in conventional manner:

(E)-S-(indol-3-ylmethylene)-1,3-dimethYl-2-methylimino-4-imidazolidinone S0 mg Lactose 95 mg Maize starch 100 mg Talc 4,5 mg Magnesium stearate 0,5 mg 1 Total weight 250,0 mg .

,

Claims (7)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. Process for the preparation of 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone characterized in that a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-methylimino-4-imidazolidinone, or b) 5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone is reacted with a methylating agent.
2. Process for the preparation of (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone characterized in that a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-methylimino-4-imidazolidinone, and the E-product is separated from the resulting E-Z mixture; or b) (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone is reacted with a methylating agent.
3. Process for the preparation of (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone characterized in that a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-methylimino-4-imidazolidinone, and the Z-product is separated from the resulting E-Z mixture; or b) (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone is reacted with a methylating agent.
4. Process for the preparation of (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone characterized in that a) indole-3-aldehyde is condensed with 1,3-dimethyl-2-methylimino-4-imidazolidinone, the E-Z mixed product is treated to maximize the Z-product content, and the Z-product is separated from the mixture; or b) (Z)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone is reacted with a methylating agent.
5. 5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone, whenever prepared by the process as claimed in claim 1 or by an obvious chemical equivalent thereof.
6. The E-isomer of 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone, whenever prepared by the process as claimed in claim 2 or by an obvious chemical equivalent thereof.
7. The Z-isomer of 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone, whenever prepared by the process as claimed in claim 3 or 4 or by an obvious chemical equivalent thereof.
CA286,134A 1976-09-07 1977-09-06 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4- imidazolidinone Expired CA1096385A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB36997 1976-09-07
GB36997/76A GB1567911A (en) 1976-09-07 1976-09-07 5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone

Publications (1)

Publication Number Publication Date
CA1096385A true CA1096385A (en) 1981-02-24

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Country Link
US (1) US4195179A (en)
CA (1) CA1096385A (en)
DE (1) DE2740151A1 (en)
DK (1) DK142414B (en)
GB (1) GB1567911A (en)
IT (1) IT1084226B (en)
PH (1) PH13622A (en)
ZA (1) ZA775365B (en)

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JP4570857B2 (en) * 2003-03-31 2010-10-27 富士フイルム株式会社 Photosensitive composition and planographic printing plate precursor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2833771A (en) * 1958-05-06 Process for the preparation of
US1849576A (en) * 1926-02-13 1932-03-15 Hoffmann La Roche Glucoside of adonis vernalis l. and process for making same
US2364041A (en) * 1942-01-05 1944-11-28 Burton T Bush Inc Process of preparing musk materials and product thereof
US2431127A (en) * 1944-04-29 1947-11-18 Gen Foods Corp Process of treating cashew nut shell liquid
US3441563A (en) * 1958-08-22 1969-04-29 Bayer Ag Process for the production of substituted pyrazolones and of monomethine dyestuffs thereof
US3904629A (en) * 1970-07-17 1975-09-09 American Home Prod 4-alkyl cycloalkyl-1-piperazino-imidazolidin-2-ones or thiones
SU485113A1 (en) * 1974-02-22 1975-09-25 Химико-Металлургический Институт Ан Казахской Сср The method of obtaining skatilgidantoina

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GB1567911A (en) 1980-05-21
DE2740151A1 (en) 1978-03-16
DK142414B (en) 1980-10-27
PH13622A (en) 1980-08-07
IT1084226B (en) 1985-05-25
US4195179A (en) 1980-03-25
DK142414C (en) 1981-03-23
ZA775365B (en) 1978-07-26

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